Subclinical thyroid dysfunction, defined as an abnormal thyroid stimulating hormone level with a normal free thyroxine level, is common in older individuals. A wide variety of systemic effects are possible from disturbances in thyroid hormone status, due to the location of thyroid hormone receptors throughout the body and the important role that thyroid hormone plays in metabolism. The appropriate clinical management of subclinical thyroid dysfunction is controversial, in large part due to major limitations in the published observational studies and a lack of data from large randomized clinical trials. Our central hypothesis is that older individuals with persistent subclinical hyperthyroidism are at increased risk for specific adverse cardiovascular, musculoskeletal, and neurocognitive outcomes, whereas those with persistent subclinical hypothyroidism are not. We propose to conduct analyses using banked blood and existing outcome data over a 19-year follow-up period in the Cardiovascular Health Study, an established, NIH-sponsored longitudinal study of community-dwelling men and women aged 65 and over. In our first aim, we will examine natural history of thyroid function testing in this population. In our second aim, we will examine the relationship between persistent subclinical hyperthyroidism and incident atrial fibrillation, hip fracture, and dementia, and in our third aim, we will examine the relationship between persistent subclinical hypothyroidism and incident coronary heart disease, congestive heart failure, and dementia. Thyroid hormones are the seventh most commonly prescribed drugs in the US, and frequently are not appropriately monitored. In our fourth aim, we will define the frequency and adverse consequences of overreplacement with thyroid hormone therapy in an older population. We will examine the same outcomes as in aim 2, to ascertain whether the effects of endogenous and exogenous subclinical hyperthyroidism are similar. By the end of the proposed study period, we will have assembled sufficient data to guide clinical management of both endogenous and exogenous subclinical thyroid dysfunction and to refine the target population and overall design of randomized, controlled clinical trials of therapy for subclinical thyroid dysfunction. This research will resolve several areas of intense controversy in the field and set the stage for definitive guidelines for management of subclinical thyroid dysfunction. PUBLIC HEALTH RELEVANCE: Subclinical thyroid dysfunction, defined as high or low thyroid stimulating hormone levels with normal free thyroid hormone levels, is common in older people. However, once these testing abnormalities are discovered, there is controversy regarding appropriate management. Our findings will assess the anticipated risks and benefits of treatment using existing data, to refine the target population for a clinical trial.